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Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2021
- Publisher :
- Rockefeller University Press, 2021.
-
Abstract
- Sharma et al. present a treatment strategy by simultaneously depleting breast cancer CAFs and tumor angiogenic vessels using a rationally designed protein that induces integrin αvβ3 target-specific cell apoptosis. This offers a unique opportunity for TNBC treatment, especially for patients with dense tumor stroma.<br />Fibrotic tumor stroma plays an important role in facilitating triple-negative breast cancer (TNBC) progression and chemotherapeutic resistance. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces apoptosis via the integrin. Cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in TNBC tumor express high levels of integrin αvβ3. ProAgio effectively induces apoptosis in CAFs and aECs. The depletion of CAFs by ProAgio reduces intratumoral collagen and decreases growth factors released from CAFs in the tumor, resulting in decreased cancer cell proliferation and apoptotic resistance. ProAgio also eliminates leaky tumor angiogenic vessels, which consequently reduces tumor hypoxia and improves drug delivery. The depletion of CAFs and reduction in hypoxia by ProAgio decreases lysyl oxidase (LOX) secretion, which may play a role in the reduction of metastasis. ProAgio stand-alone or in combination with a chemotherapeutic agent provides survival benefit in TNBC murine models, highlighting the therapeutic potential of ProAgio as a treatment strategy.<br />Graphical Abstract
- Subjects :
- 0301 basic medicine
Paclitaxel
Angiogenesis
Immunology
Integrin
Mice, Nude
Lysyl oxidase
Angiogenesis Inhibitors
Antineoplastic Agents
Apoptosis
Triple Negative Breast Neoplasms
Article
Metastasis
Protein-Lysine 6-Oxidase
03 medical and health sciences
Mice
0302 clinical medicine
Cancer-Associated Fibroblasts
Cell Line, Tumor
medicine
Immunology and Allergy
Animals
Humans
Solid Tumors
Hypoxia
Triple-negative breast cancer
Mice, Inbred BALB C
biology
Tumor hypoxia
Neovascularization, Pathologic
Chemistry
Endothelial Cells
medicine.disease
Integrin alphaVbeta3
Xenograft Model Antitumor Assays
Tumor Burden
030104 developmental biology
Treatment Outcome
Doxorubicin
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 15409538 and 00221007
- Volume :
- 218
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....6842454f49651c825ad1c3c4ee7ef6a0